Big Think hosted a panel discussion highlighting cutting-edge Alzheimer's disease research as part of our Breakthroughs series, made possible by Pfizer.
This conversation features back-and-forth exchanges between top luminaries in the field, including Dr. Samuel Gandy, Mount Sinai Professor of Alzheimer's Disease Research; Dr. Leonard Guarente, Director of Glenn Lab for Science of Aging at MIT; Dr. Juan Troncoso, Director of the Brain Resource Center at Johns Hopkins University School of Medicine; and Dr. Ottavio Arancio, Professor of Pathology & Cell Biology at the Columbia University Medical Center. The panel was moderated by Meryl Comer, President of the Geoffrey Beene Foundation Alzheimer’s Initiative.
Will Everyone Get Alzheimer’s If They Live Long Enough?
Meryl Comer: From a population perspective, 85-plus is the fastest-growing segment of the population. Now can we assume that everyone who lives long enough will get Alzheimer’s, Dr. Guarente?
Dr. Guarente: Well I don’t think we know for sure, but my guess would be that the answer is no and I base that on the fact that there is a population of people now called centenarians, who are people who live to be 100 and longer, and many of these people are in quite good health physically and mentally and have evidently escaped from all of the major diseases, including Alzheimer’s. Now, that said, I think it’s certainly true that many, many people, maybe most people would get Alzheimer’s. So from a societal point of view I think the answer is most people would be vulnerable, but from a scientific point of view I think there might be people who are just so resistant to these diseases, including Alzheimer’s that they would escape it.
Meryl Comer: Dr. Gandy, 85, 1 out of 2 gets the disease. Do you want to comment further on that?
Dr. Gandy: Well there are a handful of people who live to 120, so then they’ve been characterized neuro-psychologically near the time of death and then studied pathologically and it’s possible for some people with the right genes to live to 120 and be cognitively intact and have absolutely clean brains, have no Alzheimer’s pathology.
Meryl Comer: But let’s...
Dr. Arancio: Maybe even live to be 150.
Dr. Gandy: It’s possible if everyone lived to 150 then everyone would get Alzheimer’s disease, but 120 is not the 100%. It may even be 99%, but it’s not 100%.
Meryl Comer: Well let’s help our audience move along a progression from mild cognitive impairment and that trajectory that takes you to Alzheimer’s, which is just the most common form of dementia. Can you help us, take us down that road?
Dr. Gandy: Mild cognitive impairment is really the first sort of syndrome that neurologists will diagnose that might be related to Alzheimer’s disease. Mild cognitive impairment usually means there is a problem with memory and it may be isolated to just memory and if it’s called mild cognitive impairment or MCI, by the abbreviation, it usually implies that the person’s normal function is not impaired, so that they can compensate for it and continue to do their normal tasks in their regular lives. The prognosis of mild cognitive impairment has long been sort of a mystery because it was some people seem to live through MCI and never get Alzheimer’s disease while some actually went on from MCI to progress to dementia, which was usually Alzheimer’s disease. We now we learned just this past summer that there are spinal fluid tests that might be able to help us predict which people with MCI are on their way to Alzheimer’s disease.
Meryl Comer: But the majority of people in assisted living facilities today, 60% have MCI that put them in there in the first place. What's their trajectory onto Alzheimer’s?
Dr. Gandy: Well without this sort of spinal fluid evidence we can’t really predict. That is part of why the Food and Drug Administration hasn’t allowed us to use MCI as a diagnosis because the prognosis of MCI as a group is unknown. Some people stay unchanged. Some get worse. Some get better.
Dr. Arancio: It’s about 18% every 2 years that go from MCI to Alzheimer’s.
Meryl Comer: And what happens with your patients with Parkinson’s plus dementia? Does Alzheimer’s or dementia come at the end of the disease like Parkinson’s or frontal lobe...?
Dr. Troncoso: Well in the case of Parkinson’s disease, from a clinical perspective once that individual has had probably 8, 10 years of the disease is at high risk of having some sort of dementia, which is actually different from the Alzheimer’s disease. It’s not the same type of manifestation. It’s not so problem with memory for instance, but it’s a difficulty in getting tasks performed. Kind of they are very slow in performing tasks. Having said that the substrate, the reason why patients with Parkinson’s disease have dementia is not clear. Furthermore, because these are diseases of aging many patients that have Parkinson’s disease also have Alzheimer’s disease, and probably both disorders add their lesions to render the patient demented. That is why it would be very important perhaps to slow down the aging process. You would kill two birds with one stone. You would actually prevent both Parkinson’s and Alzheimer’s disease.
Dr. Guarente: It would be more than two because we all have vulnerabilities and resistances and if we are resistant to one thing we’re going to be sensitive to something else.
Dr. Troncoso: Exactly.
Dr. Guerente: Aging is going to cause something bad to happen.
The Brain Plaques and Tangles That Cause Alzheimer’s
Meryl Comer: The mainstream research has been focused on beta amyloid. Tau has always been there, but now there is a big controversy about where the progression comes, where does it really lie? Take that debate on Dr. Gandy.
Dr. Gandy: Well certainly people with Alzheimer’s disease have two sorts of lesions in their brains, two sorts of clumps of protein. Some of these clumps are in between nerve cells, and others are inside nerve cells. The ones that are in between the nerve cells are called amyloid plaques. The clumps that are inside the nerve cells, which are twisted, are called tangles or neurofibrillary tangles. Now for many years we didn’t sort of know what the sequence of events was, but it is very clear now that all the genes that cause Alzheimer’s disease point to the buildup of amyloid. So it appears that Alzheimer’s disease amyloid comes first and tangles come next. They may be extremely important in understanding why the nerve cell dies. Now the disease that Dr. Troncoso mentioned, frontal temporal dementia, has also helped us to understand the relationship between plaques and tangles because in that disease the mutations that cause the genetic forms are in the protein called tau that builds up and causes tangles. People with frontal temporal dementia get tangles, but they never get plaques, so in Alzheimer’s disease plagues can cause tangles, but in frontal temporal dementia tangles don’t cause plaques.
Meryl Comer: Well why is it so hard these days to get a grant from NIA around beta amyloid when you can get it for tau?
Dr. Gandy: Well so there is a specific reason for that that’s really evolved a lot in the last year. There is a study that was reported this spring that showed using an antibody, a chemical aimed at the amyloid substance... that if people with mild Alzheimer’s disease received antibody infusions, anti-amyloid infusions, for a year and a half that the amyloid buildup in their brains would go down by about 25%. They didn’t change at all clinically. They didn’t get any better in terms of their cognitive function. Why is that? Because we didn’t start early enough, because we didn’t treat long enough or because it’s actually another form of amyloid, not the plaques, but these floating clumps called oligomers?
Meryl Comer: You wanted to make a point, yes, doctor.
Dr. Troncoso: Yeah well, I think that there is a lot of debate between the amyloid and tau deposition, but I think one should not get stopped at that point of that argument because it’s perfectly possible that one of these abnormalities, let’s say amyloid may trigger the rest and there is more than amyloid and tau. We haven’t spoken, but there is a very significant inflammatory, inflammation in the brain that once you have perhaps amyloid and tau trigger that event it becomes self-sufficient. It actually may even promote more amyloid or more tau deposition, so I think that tau it may be as important as amyloid, but it may be later on in this progression of the disease. And if you could actually target each of these elements it probably would be beneficial. So I don’t see really a tremendous dichotomy, antagonism between looking at amyloid and tau. I think that both are perfectly legitimate targets of research and one more perhaps disgression in terms of the dementia that is being seen in patients who have head trauma. Most of that, the lesions that they have is of the tau type, so I think both of these targets amyloid and tau should be addressed. There is no reason to eliminate one of them.
Dr. Gandy: There is the one experiment to mention that might also explain why the shift sort of toward tau. A lot of what we’ve learned about Alzheimer’s disease is from mouse models. Mice normally never ever get Alzheimer’s disease because their amyloid is different enough that it doesn’t clump and build up. If we then put into a mouse the gene for amyloid and with a mutation that would cause it to build up and the gene for tau so that it will get tangles, then as that animal ages it will get buildup of plaques and tangles just like, similar to humans with Alzheimer’s disease. They will then lose their ability to find their way around their cage or to find their way around a swim maze. If you then treat them with a drug or substance that will decrease the levels of tau, will lower the tau down, the cognitive function comes back, so it’s possible to sort of render the amyloid inert if you can turn down the tau at least in the mouse model.